Dexamethasone Suppression Test

Types of dexamethasone suppression tests include high-dose suppression and low-dose suppression tests. Normal findings in prolonged testing include the following ^[1] :

• Low dose: >50% reduction of plasma cortisol
• High dose: >50% reduction of plasma cortisol
• Urinary free cortisol: < 20 mcg/24 hr (< 50 nmol/24 hr)

In the rapid (overnight) test, normal results find plasma cortisol levels suppressed to < 2 mcg/dL. ^[1]

Cushing syndrome encompasses all causes of glucocorticoid excess, whereas Cushing disease is reserved only for pituitary-dependent Cushing syndrome.

Low-dose dexamethasone suppression test

Suppression is absent in Cushing syndrome.

False-positive results can occur in the following situations:

• Estrogens in oral contraceptive pills increase cortisol-binding globulin leading to an increase in total cortisol. Women who are taking oral contraceptive pills should discontinue use 6 weeks prior to the test.

• Phenytoin, phenobarbitone, carbamazepine, rifampicin, and alcohol can induce CYP3A4 and increase hepatic clearance of dexamethasone.

Suppression is present in healthy subjects.

False-negative results can occur in subjects with Cushing syndrome in the following situations:

• Patients with nephrotic syndrome, because of the drop in albumin and cortisol-binding globulin

• Patients with liver failure and/or renal failure

• Patients on drugs that inhibit CYP3A4 and decrease hepatic clearance of dexamethasone (eg, aprepitant/fos aprepitant, itraconazole, ritonavir, fluoxetine, diltiazem, cimetidine)

High-dose dexamethasone suppression test

Suppression is absent in patients with Cushing syndrome due to ectopic ACTH secretion or adrenal abnormalities. Suppression is present in patients with Cushing disease.

Specifics for collection and panels of dexamethasone suppression tests are as follows:

Serum cortisol

See the list below:

• Patient instruction: Preferred in the morning, no fasting needed

• Specimen type: Blood serum

• Collection tube: Red-top tube or gel-barrier tube

• Unacceptable conditions: Grossly hemolyzed specimens

• Specimen preparation: Plasma should be separated and transferred to a transport tube

• Storage/transport temperature: Refrigerated

Panels: None

24 -hour urinary free cortisol

See the list below:

• Patient instruction: Collection usually starts in the morning; the patient discards the first void and then collects all urine for the next 24 hours (including the first void the next morning)

• Collection : Plastic urine containercontaining 1g of boric acid per liter

• Specimen preparation: Urine creatinine should be measured in the same specimen to assess adequacy

• Storage/transport temperature: Refrigerated

Panels: None

Description

Dexamethasone is a synthetic glucocorticoid that does not interact with cortisol measurement. ^{[2, 3, 4, 5]}

Low-dose dexamethasone suppression tests

In a subject with a normal hypothalamic–pituitary–adrenal (HPA) axis, a supraphysiological dose of dexamethasone can inhibit ACTH secretion by the pituitary leading to drop in cortisol level in serum, urine and saliva; such inhibition does not occur in patients with Cushing syndrome.

• Overnight suppression test: Administer 1 mg oral dexamethasone between 11 pm and midnight. Test cortisol level between 8 am and 9 am the next morning.

• Standard 2-day dexamethasone suppression test: Administer 0.5 mg oral dexamethasone every 6 hours for 48 hours (9 am, 3 pm, 9 pm, and 3 am). Measure cortisol level 6 hours (9 am) after the last dose. Other protocols suggest starting dexamethasone 0.5 mg orally every 6 hours starting at noon for 48 hours and checking cortisol level 2 hours (8 am) after the last dose.

The 24-hour urine free cortisol test may be used during the second day of the standard test as an end point; however, data suggest that serum cortisol has higher diagnostic accuracy and conducting both tests is not recommended. ^[6]

High-dose dexamethasone suppression test

In subjects with Cushing disease, a higher dose of dexamethasone (usually 8 mg) is required to suppress ACTH secretion and drop cortisol level in serum, urine, and saliva.

• Standard 2-day dexamethasone suppression test: Serum cortisol level and/or 24-hour urinary free cortisol is measured as a baseline, and then dexamethasone 2 mg orally is taken every 6 hours for 48 hours; urine for free cortisol is collected during the test and serum cortisol is checked 6 hours after the last dose.

• Overnight suppression test: Serum cortisol is checked at baseline, then dexamethasone (typically 8 mg) is given orally between 11 pm and midnight. Cortisol level is then checked between 8 am and 9 am the next morning.

• Intravenous dexamethasone suppression test: Serum cortisol is checked at baseline, followed by continuous infusion of intravenous dexamethasone at a rate of 1 mg/h for 5-7 hours.

Indications/Applications

The low-dose dexamethasone suppression test is one of the screening tests for Cushing syndrome. Four highly sensitive tests are recommended by the Endocrine Society for the screening of Cushing syndrome: 24-hour urinary free cortisol, late-night salivary cortisol, overnight dexamethasone suppression test, and sta  ndard 2-day dexamethasone suppression test. ^[7] If Cushing syndrome is suspected, the physician should perform at least two 24-hour urinary free cortisol tests, at least 2 late-night salivary cortisol tests, or one dexamethasone suppression test. If this initial evaluation is positive, then another set of tests should be performed.

The high-dose dexamethasone suppression test is used in patients with confirmed Cushing syndrome when further workup is needed to identify the etiology. The first step is to differentiate between ACTH-dependent Cushing syndrome (ectopic ACTH and Cushing disease) and ACTH-independent Cushing syndrome (adrenal disorders). Once the Cushing syndrome is confirmed to be ACTH-dependent, a high-dose dexamethasone suppression test is performed to differentiate between Cushing disease (suppression) and ectopic ACTH.

The causes of ACTH-dependent Cushing syndrome are as follows:

• Cushing disease

• Macronodular Adrenal Hyperplasia (can occur in patients with Cushing disease as a result of ACTH excess)

• Ectopic ACTH syndrome

• Small cell lung cancer

• Non-small cell lung cancer

• Pancreatic tumors

• Neuroendocrine tumors including lung carcinoids, pheochromocytoma, and medullary thyroid cancer

The causes of ACTH-independent Cushing syndrome are as follows:

• Iatrogenic

• Adrenal adenoma/carcinoma

• Carney syndrome and primary pigmented nodular adrenal hyperplasia

• McCune-Albright syndrome

Considerations

Pseudo-Cushing syndrome can occur as a result of the following conditions:

• Depression, anxiety disorder, obsessive compulsive disorder

• Alcohol dependence

• Morbid obesity

• Poorly controlled diabetes mellitus

These conditions can overactivate the HPA axis, causing a physiological increase in circulating cortisol and leading to erroneous dexamethasone suppression test results and/or elevated 24-hour urinary free cortisol levels suggestive of Cushing syndrome.

The standard 2-day low-dose dexamethasone suppression test followed by corticotropin-releasing hormone (CRH) was designed to differentiate between Cushing syndrome and pseudo-Cushing syndrome.

The test is performed by administering 0.5 mg dexamethasone orally every 6 hours for 48 hours followed by IV CRH (1µg/kg) 2 hours after the last dose of dexamethasone; then cortisol level is measured about 15 minutes after IV CRH administration. Patients with Cushing syndrome do not suppress, whereas patients with pseudo-Cushing syndrome do suppress their cortisol level.

According to The Endocrine Society, this test can be useful in patients with equivocal 24-hour urinary free cortisol results, and a dexamethasone level should be measured at the time of CRH administration to exclude a false-positive result. ^[7]